[Methodological recommendations for surgical care in patients with hemophilia A receiving prophylactic therapy with emicizumab]. / Metodicheskie rekomendatsii po okazaniyu khirurgicheskoi pomoshchi u patsientov s gemofiliei A, poluchayushchikh profilakticheskuyu terapiyu emitsizumabom.

Methodological recommendations for surgical care in patients with hemophilia A receiving prophylactic therapy with emicizumab. Recommendations of the expert group. Moscow, 2024.

Paradox pain sensitivity using cuff pressure or algometer testing in patients with hemophilia.

INTRODUCTION: Pain is a common comorbidity in patients with hemophilia (PwH) due to hemophilic arthropathy. This study aims to explore pain sensitivity in PwH methodologically investigating in cuff pressure testing compared to algometer testing. METHODS: 37 PwH and 35 healthy control subjects (Con) enrolled in this study. Joint health status was assessed. Subjective pain was evaluated using numeric rating scales. Pain sensitivity was measured with pressure algometry and cuff pressure algometry. Pressure pain thresholds of the algometer (PPTa) were measured at knee, ankle joints, and forehead. Subsequently, thresholds of cuff pressure were measured at the left and right lower legs (PPTcuff). In both, lower values represent higher pain sensitivity. RESULTS: PwH exerted a worse joint health status than Con. Pain sensitivity was higher in PwH compared to Con as PPTa of the knee and ankle joints were lower in PwH. No difference was observed in PPTa at the forehead. Contrastingly, lower pain sensitivity was detected in PwH by higher PPTcuff values compared to Con in both legs. CONCLUSION: While PPTa of the knee and ankle joints are lower in PwH, PPTcuff are higher in PwH compared to Con. This reveals a paradox situation, highlighting that PwH experience local, joint- and hemophilic arthropathy-related pain, whereas pain sensitivity of non-affected soft tissue structures is lower. The reasons explaining the PPTcuff results remain elusive but might be explained by coping strategies counteracting chronic joint pain, resulting in lower sensitivity at non-affected structures.

Assessment of jaw bone mineral density, resorption rates, and oral health in patients with severe hemophilia: a case-control study.

OBJECTIVE: Knowledge about oral hygiene, gingival bleeding, mineral density, and resorption of jaw bones in patients with hemophilia is limited. We evaluated the periodontal and bone status in such patients.  Material and methods: Forty-eight patients with severe type A/B hemophilia and 49 age- and sex-matched controls were included. Assessments included simplified oral hygiene index (OHI-S), calculus index, debris index, gingival index (GI), gingival bleeding time index (GBTI), and decayed, missing, and filled teeth index (DMFTI). Bone resorption was evaluated using panoramic mandibular index (PMI), mental index (MI), and alveolar crest ratio (ACR). Mineral density in the condyle, angulus, and premolar areas was assessed using fractal analysis, with fractal dimensions denoted as condyle fractal dimension (CFD) for the condyle, angulus fractal dimension (AFD) for angulus, and premolar fractal dimension (PFD) for premolar region. RESULTS: The mean scores were DMFTI = 11.77, OHI-S = 2.44, PMI = 0.268, MI = 5.822, GI = 3.02, GBTI = 2.64, ACR = 2.06, CFD = 1.31, AFD = 1.31, and PFD = 1.17 in the hemophilia group and DMFTI = 11.449, PMI = 0.494, MI = 7.43, GI = 0.67, GBTI = 0.98, OHI-S = 1.45, ACR = 2.87, CFD = 1.35, AFD = 1.35, and PDF = 1.23 in the control group. Differences were significant for all parameters (p < 0.005) except for the DMFTI index.  Conclusions: Because of poor oral hygiene, high bone resorption, and low bone mineral density in these patients, clinicians should consider potential bone changes when planning to treat these patients.

Acquired bleeding disorders.

Acquired bleeding disorders can develop in previously healthy people irrespective of age or gender but are particularly common in patients with certain underlying conditions. Here, we review recent advances in the management of acquired haemophilia A (AHA), acquired von Willebrand syndrome (AVWS), and patients with hemostatic abnormalities due to chronic liver disease (CLD). Patients with AHA can now benefit from prophylaxis with emicizumab, a therapeutic antibody that mimics the function of activated coagulation factor VIII. The treatment of AVWS remains challenging in many situations and requires careful consideration of the underlying condition. Haemostatic abnormalities in CLD are often compensated by proportional reduction in pro and anti-haemostatic factors resulting in sustained or even increased thrombin generation. Consequently, bleeding in CLD is rarely caused by haemostatic failure and infusion of plasma or coagulation factor concentrates may not be effective.

Haemophilic arthropathy: Diagnosis, management, and aging patient considerations.

Gene therapy and universal use of safer, more effective, and personalised prophylactic regimens (factor, and nonfactor) are expected to prevent joint bleeding and promote joint health in persons with haemophilia (PwH). Growing evidence suggests that subclinical bleeding, with active and inactive synovial proliferation, continues and haemophilic arthropathy remains a major morbidity in PwH despite early institution of joint prophylaxis. Joint health assessment is evolving with physical examination scores complementing imaging scores. Point-of-care ultrasound is emerging as a safe, cost-effective, and readily available tool for acute determination of musculoskeletal abnormalities, serial evaluation of joints for sonographic markers of haemophilic arthropathy, and in providing objective insight into the efficacy of new therapies. In acute haemarthrosis, arthrocentesis expedites recovery and prevent the vicious cycle of bleed-synovitis-rebleed. When synovial proliferation develops, a multidisciplinary team approach is critical with haematology, orthopaedics, and physiotherapy involvement. Synovectomy is considered for patients with chronic synovitis that fail conservative management. Non-surgical and minimally invasive procedures should always be offered and considered first. Careful patient selection, screening and early intervention increase the success of these interventions in reducing bleeding, pain, and improving joint function and quality of life. Chemical synovectomy is practical in developing countries, but radioactive synovectomy appears to be more effective. When surgical synovectomy is considered, arthroscopic/minimally invasive approach should be attempted first. In advanced haemophilic arthropathy, joint replacement and arthrodesis can be considered. While excited about the future of haemophilia management, navigating musculoskeletal challenges in the aging haemophilia population is equally important.

Hemophilia and hepatology, back to the future.

Years ago, patients with hemophilia were often cared for because of liver issues. The use of hemoderivatives in the 1970s and 1980s, and the natural history of chronic hepatitis B and C, led to a surge of patients with cirrhosis and related complications after two or three decades. It was not until the approval of entecavir and tenofovir (2005-2008) against the B virus, and of direct-acting antiviral agents (2015) against the C virus, that a truly effective treatment became available for liver disease. Since then, patients with hemophilia disappeared from hepatology clinics and wards, apart from specific isolated problems.

Acquired Hemophilia: A Rare Complication of Pediatric Idiopathic Multicentric Castleman Disease.

Acquired hemophilia is caused by acquired autoantibodies to 1 of the factors of the coagulation cascade, usually factor VIII or IX, and is an exceedingly rare phenomenon in children. The finding of an acquired factor VIII inhibitor in a pediatric patient with idiopathic multicentric Castleman disease has never been reported. Patients with acquired hemophilia can have life-threatening bleeds that are refractory to blood product support, requiring bypassing agents to manage bleeding symptoms. We present the novel finding of acquired hemophilia resulting from an autoantibody to factor VIII in a pediatric patient with idiopathic multicentric Castleman disease and discuss the optimal management of bleeding in a patient with acquired hemophilia.

Severe case of postpartum-acquired haemophilia A after laparoscopic cholecystectomy.

Acquired factor VIII inhibitor, also known as acquired haemophilia A, has been associated with the postpartum state in young females. Treatment of acquired haemophilia A is focused on two goals: control of bleeding and eliminating the factor VIII inhibitor. Management requires successful intervention to accomplish both goals. Here, we describe the presentation and management of a case of acquired haemophilia A resulting in particularly severe and protracted intra-abdominal bleeding after routine laparoscopic cholecystectomy in a young and otherwise healthy female at 3 months postpartum. Due to diffuse intra-abdominal bleeding, she required return to the operating room on five occasions for intra-abdominal packing, reassessment of bleeding and ultimate fascial closure. Her abdomen was open for 5 days. She was treated with activated recombinant human factor VIIa to bypass inhibited factor VIII, and with immunosuppression using steroids, cyclophosphamide and anti-CD20 monoclonal antibody rituximab. She achieved remission after 6 weeks of treatment.

Stromal cell-derived factor 1 alpha (SDF-1alfa) and cartilage oligomeric matrix protein (COMP): Two potential signature biomarkers of radiological detectable hemophilic arthropathy.

INTRODUCTION: Hemophilia is a rare constitutional bleeding disorder due to a deficiency in Factor VIII or Factor IX. Recurrent hemarthroses, one of the major complications of the disease, lead to hemophilic arthropathy, a disabling condition that requires early diagnosis. Traditionally, clinical examination and plain film radiography have been used to diagnose hemophilic arthropathy. Magnetic resonance imaging (MRI) and ultrasound can be more useful for diagnosing soft-tissue changes. However, but each of these methods has limitations and diagnosis of arthropathy can be delayed. AIM: The aim of this project was to assess plasmatic biomolecules indicative of osteo-cartilaginous damage in patients with hemophilia with or without known arthropathy, in order to improve the diagnosis of this major complication of the disease. METHODS: In this monocentric retrospective study, 40 patients with hemophilia A or B, for whom a plasma sample was available, provided informed consent for further analyses (multiplex immunoassays and ELISA) and collection of relevant clinical information in their medical files. Correlations were sought for between biomarkers of interest and the severity of joint lesions assessed according to Pettersson's radiologic score. RESULTS: Two biomarkers were identified, respectively SDF-1α and COMP. Their plasmatic levels were significantly increased in patients with arthropathy compared to controls and patients without arthropathy. These values correlated significantly with the Pettersson score in patients under regular prophylaxis. CONCLUSION: Two plasma biomarkers have been identified that could help assess the presence and severity of hemophilic arthropathy.

Women and girls with inherited bleeding disorders: Focus on haemophilia carriers and heavy menstrual bleeding.

Raising awareness and improving recognition, accurate classification, and enhanced access to new treatments represent current key challenges for carriers of haemophilia. Women and girls carrying genes for haemophilia often experience significant bleeding and/or low factor levels. The bleeding associated with female haemophilia is frequently overlooked, has a weak correlation with factor levels, and manifests differently than in males, with heavy menstrual bleeding being a predominant symptom. Recent changes in terminology now allow the diagnosis of haemophilia in females with low factor levels and differentiate between symptomatic and asymptomatic carriers of the gene. Observations from real-world experiences and limited clinical trial data have highlighted the positive impact of various new haemophilia treatments for women and girls with clotting factor deficiencies. There is an urgent need for initiatives that increase their access to these treatments and encourage well-designed clinical trials focusing on female-specific outcomes. In women with inherited bleeding disorders, early recognition and optimal management of heavy menstrual bleeding are crucial. However, treatment options and guidance from high-quality clinical trials are currently insufficient. Menstrual health assessment should be a regular part of monitoring women and girls with inherited bleeding disorders throughout their lives, emphasizing the importance of gathering data to improve future management.

Challenges in ageing persons with haemophilia.

As treatments for individuals with inherited bleeding disorders improve, life expectancy increases and is approaching that of the normal population. Concomitant with this we are now seeing the problems of ageing in the bleeding disorder population. Although the clear-cut association between low clotting factor levels and risk of bleeding is well recognised, a relationship between high levels, some non-factor therapies and thrombotic risk also exists. The management of thrombosis in persons with inherited bleeding disorders is complex but manageable with modern treatments and collaboration in decision making between health care professionals and patients. Despite the improvements in treatment and reduction in bleeding, mostly musculoskeletal pain continues to be a major issue with advancing age. The management of pain amongst older people with haemophilia who may have multiple comorbidities should involve a person-centred, holistic, multi-disciplinary approach to support and optimise long-term physical functioning and overall quality of life.

[Removal of a dermoid cyst of the floor of the mouth in a patient with severe hemophilia A]. / Udalenie dermoidnoi kisty dna rta u bol'nogo tyazheloi formoi gemofilii A.

The article presents a case of a surgical treatment of removing a dermoid cyst of the floor of the oral cavity in a patient with severe hemophilia A. A detailed analysis was carried out of the surgical operation, postoperative management, coagulation factor replacement therapy and accompanying therapy, as well as the features of anesthesia, which allowed a surgical intervention without any hemorrhagic and infectious complications.

Bone mineral density in haemophilia patients: A systematic review and meta-analysis.

INTRODUCTION: With the increase in life expectancy of haemophilia patients (PWH), the risk of osteoporosis increases, but there is little research on whether haemophilia is the cause of osteoporosis. AIM: To conduct systematically review whether bone mineral density (BMD) in PWH decreased and the factors affecting BMD. METHODS: Two authors independently searched databases and reviewed citations from relevant articles, selecting studies published in any language and performed in humans before March 2023. Eligibility criteria were observational studies in PWH, with BMD as at least one outcome other than osteoporosis or bone loss, and analyses in a group of PWH and healthy controls. RESULTS: Twelve studies were ultimately identified, consisting of 1210 individuals (534 PWH and 676 healthy controls), compared with the control group, BMD in PWH decreased by 0.13 g/cm2 [95% confidence interval (CI) -0.18 to -0.08, I2  = 89%]. No evidence of publication bias was detected. There was no evidence that age, BMI, level of physical activity, the types of haemophilia, haemophilia severity, a blood-borne virus (HCV) and treatment modality predicted the BMD in PWH. CONCLUSION: The results indicate that BMD in PWH is lower than in healthy controls. Therefore, we strongly recommend PWH early measurement of BMD to prevent osteoporosis.

A rare twist: COVID-19 infection masquerading as IgA vasculitis in a hemophilia a patient.

Hemophilia A and B are one of the most common hereditary bleeding disorders. Patients are predisposed to bleeding spontaneously or after minor trauma in different areas such as the skin, gastrointestinal, or joints. COVID-19 infection has been associated with various clinical manifestations and complications including rarely triggering IgA vasculitis. We report a 23-year-old man who was previously diagnosed with severe hereditary hemophilia A. He presented to our hospital with classic symptoms of IgA vasculitis, complaining of petechiae and purpura in his limbs, fatigue, body aches, poor oral intake, abdominal pain, and watery non-bloody diarrhea. He did not present with respiratory symptoms or fever typical of COVID-19 infection. Abnormal blood tests were mildly elevated C-reactive protein, elevated d-dimers, and low Factor VIII activity. Extensive immunological tests were negative. CT abdomen with contrast was unremarkable. A skin biopsy strongly indicated IgA vasculitis. COVID-19 test came back positive. The patient was managed symptomatically and with glucocorticosteroids which significantly improved his symptoms. The available literature on clinical features, laboratory tests, and management of COVID-19-associated IgA vasculitis is discussed. However, there is no case reported on the associations between hemophilia, COVID-19 infection, and IgA vasculitis. This is the first case of atypical COVID-19 infection masquerading as de novo IgA vasculitis in an adult patient with underlying hemophilia. Our case contributes to the growing body of literature about hemophilia being a possible predisposing factor that a COVID-19 virus relies on to amplify immune dysregulation resulting in IgA vasculitis.

Arthroscopic ankle surgery in people with haemophilia.

INTRODUCTION: People with haemophilia (PWH) not administered primary haematological prophylaxis since childhood, that is, those treated haematologically on demand or not treated at all, often experience the degeneration of the ankles, leading to pain and functional impairment. AIM: To analyse the outcomes and complications of arthroscopic ankle surgery performed on PWH. METHODS: For this narrative review of the literature, a search was conducted in PubMed on 2, December 2023, using the keywords "haemophilia", "ankle" and "arthroscopy". Of the 29 articles identified, 15 specifically related to ankle arthroscopy in PWH were selected (inclusion criterion). The remaining articles did not meet this requirement (exclusion criterion) and were therefore eliminated. RESULTS: Arthroscopic procedures (arthroscopic synovectomy, debridement and arthrodesis of the ankle) are increasingly used in the surgical treatment of haemophilic ankle arthropathy. Although arthroscopic ankle surgery offers good outcomes in patients with haemophilia, the procedure is not free of complications, which range from 7.9% for arthroscopic ankle debridement to 13.1% in arthroscopic ankle synovectomy and 17.8% in arthroscopic ankle arthrodesis, respectively. The non-union rate of arthroscopic ankle arthrodesis is 7.1% (2/28). CONCLUSION: Although arthroscopic interventions in the haemophilic ankle (synovectomy, debridement, arthrodesis) offer good functional outcomes, they are associated with a non-negligible rate of complications. Arthroscopic ankle surgery in PWH is major surgery and should be treated as such.

Long-term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6 years post-treatment.

INTRODUCTION: Valoctocogene roxaparvovec uses an adeno-associated virus serotype 5 (AAV5) vector to transfer a factor VIII (FVIII) coding sequence to individuals with severe haemophilia A, providing bleeding protection. AIM: To assess safety and efficacy of valoctocogene roxaparvovec 5-6 years post-treatment. METHODS: In a phase 1/2 trial, adult male participants with severe haemophilia A (FVIII ≤1 IU/dL) without FVIII inhibitors or anti-AAV5 antibodies received valoctocogene roxaparvovec and were followed for 6 (6 × 1013 vg/kg; n = 7) and 5 (4 × 1013 vg/kg; n = 6) years. Safety, including investigation of potential associations between a malignancy and gene therapy, and efficacy are reported. RESULTS: No new treatment-related safety signals emerged. During year 6, a participant in the 6 × 1013  vg/kg cohort was diagnosed with grade 2 parotid gland acinar cell carcinoma; definitive treatment was uncomplicated parotidectomy with lymph node dissection. Target enrichment sequencing of tumour and adjacent healthy tissue revealed low vector integration (8.25 × 10-5 per diploid cell). Integrations were not elevated in tumour samples, no insertions appeared to drive tumorigenesis, and no clonal expansion of integration-containing cells occurred. During all follow-ups, >90% decreases from baseline in annualised treated bleeds and FVIII infusion rates were maintained. At the end of years 6 and 5, mean FVIII activity (chromogenic assay) was 9.8 IU/dL (median, 5.6 IU/dL) and 7.6 IU/dL (median, 7.1 IU/dL) for the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, representing proportionally smaller year-over-year declines than earlier timepoints. CONCLUSIONS: Valoctocogene roxaparvovec safety and efficacy profiles remain largely unchanged; genomic investigations showed no association with a parotid tumour.